Dale E Fowler

University of Alabama at Birmingham, Birmingham, Alabama, United States

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Publications (3)10.34 Total impact

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    ABSTRACT: Adrenomedullin (AM) is a recently discovered, potent vasodilatory peptide with activities including maintenance of cardiovascular and renal homeostasis. Studies have indicated that AM is important in initiating the hyperdynamic response during the early stage of sepsis, and reduction of the vascular effects of AM marks the transition from the initial hyperdynamic phase to the late hypodynamic phase in experimental sepsis. The decreased AM responsiveness in late sepsis may be related to alterations in the AM receptor binding characteristics and/or signaling pathways. Genetic experiments have provided useful information by enhancing AM gene expression. Moreover, a plasma protein which binds AM, adrenomedullin binding protein-1 (AMBP-1), was reported very recently and is just beginning to be investigated as an important modulator in the biphasic septic response. In this regard, our recent results have demonstrated that AMBP-1 synergistically enhanced AM-induced vascular relaxation in both sham and septic animals. It appears that decreased levels of AMBP-1 play a critical role in producing vascular AM hyporesponsiveness during the late stage of sepsis. Furthermore, administration of AM and AMBP-1 in combination prevented the transition from the hyperdynamic to hypodynamic response during the progression of polymicrobial sepsis. Thus, modulation of vascular responsiveness to AM by AMBP-1 may provide a novel approach for the management of sepsis.
    No preview · Article · Mar 2003 · Journal of Surgical Research
  • Shaolong Yang · Mian Zhou · Dale E Fowler · Ping Wang
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    ABSTRACT: Our recent study indicates that administration of adrenomedullin (AM) in combination with AM-binding protein-1 (AMBP-1) before sepsis (i.e., pretreatment) maintains cardiovascular stability and reduces the mortality rate. The aim of the present study was to determine whether administration of AM/AMBP-1 after the onset of sepsis (posttreatment) has any salutary effects on the septic host, and if so, whether AM/AMBP-1 down-regulates proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6. Prospective, controlled, randomized animal study. A university research laboratory. Male adult Sprague-Dawley rats. Rats were subjected either to polymicrobial sepsis by cecal ligation and puncture or to sham operation followed by the administration of normal saline solution (i.e., fluid resuscitation). At 5 hrs after cecal ligation and puncture, AM (12 microg/kg body weight) and AMBP-1 (40 microg/kg body weight) were administered intravenously over 1 hr. At 20 hrs after cecal ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac output, stroke volume, total peripheral resistance, systemic oxygen delivery, and organ blood flow were determined by radioactive microspheres, and circulating concentrations of proinflammatory cytokines were measured using enzyme-linked immunosorbent assay kits. Moreover, plasma concentrations of transaminases and lactate were measured. The results indicated that administration of AM/AMBP-1 at 5 hrs after cecal ligation and puncture prevented the decrease in measured systemic and regional hemodynamic variables and reduced plasma concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 at 20 hrs after the onset of sepsis. Moreover, administration of AM/AMBP-1 attenuated hepatic damage and the increase in plasma lactate and prevented hemoconcentration. Administration of AM/AMBP-1 may provide a novel approach to the treatment of sepsis. Moreover, because AM/AMBP-1 significantly reduced circulating concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, down-regulation of those proinflammatory cytokines by AM/AMBP-1 appears to play an important role for the beneficial effects of these agents in polymicrobial sepsis.
    No preview · Article · Jan 2003 · Critical Care Medicine
  • Dale E Fowler · Ping Wang
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    ABSTRACT: Sepsis and its complications are leading causes of morbidity and mortality. A better understanding of the mechanisms responsible for the shift from the early, hyperdynamic phase of sepsis to the late hypodynamic phase could lead to novel therapies that might improve the outcome of the septic patient. Adrenomedullin is a vasodilatory peptide which shows sustained elevation starting early in sepsis and is important in initiating the hyperdynamic response. As sepsis progresses, however, the vascular response to adrenomedullin is blunted and this decreased sensitivity is important in producing the shift to the late, hypodynamic phase. The decline in the vascular response to adrenomedullin is related to a sepsis-induced decrease in the binding protein for adrenomedullin (i.e., adrenomedullin binding protein-1) rather than a change in gene expression of the components of adrenomedullin receptors. Treatment of septic animals with the combination of adrenomedullin and its binding protein prevents the transition to the late phase of sepsis, maintains cardiovascular stability, and reduces sepsis-induced mortality. We propose that the mechanisms responsible for the beneficial effect of adrenomedullin and adrenomedullin binding protein-1 in sepsis are associated with downregulation of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), maintainence of endothelial constitutive nitric oxide synthase, and reduction of vascular endothelial cell apoptosis.
    No preview · Article · Jun 2002 · International Journal of Molecular Medicine